the ANRS CO21 " Extreme " Cohort (CODEX)

Two cohorts of patients with a phenotype of HIV resistance exist in France. The ANRS CO15 ALT cohort was set up in 1994. 71 patients were enrolled defined on immunological criteria: CD4 T cell count above 600/mm3 with a stable or increasing count (positive or zero slopes) on at least three consecutive exams performed during the last 5 years whatever the viral load was, with a known HIV infection for at least 8 years. A consortium of research teams has studied the immunovirological characteristics of these patients. After 16 years of follow-up, 6 patients are still actively followed. The main results have shown the lack of deletion in viral genes nor any functional viral defects, a small size for the viral reservoir, and distinctive genetic characteristics of the host (HLA, chemokines) which lead to potent immune cell responses associated with virus control.

The ANRS CO18 HIV Controller cohort set up in 2009 is stemming from the French National Observatory of HIV Controllers which was active between 2006 and 2008 (Study ANRS EP36). 152 patients are enrolled who are defined on virological criteria: the last 5 plasmatic viral loads should be below 400 copies/mL without any antiretroviral treatment, in HIV-infected patients for more than 5 years. A consortium of research teams has studied these patients and has shown that Controllers are infected with replication-competent HIV, that HIV infects CD4 T cells but that the viral replication in CD4 T cells is fully controlled by CD8 T cells.

In addition, the ANRS EP47 VISCONTI study identified 14 patients who had been able to maintain plasmatic viral loads below 400 copies/ml for more than 7 years in the absence of antiretroviral treatment. Differently from HIV controllers, naïve of antiretroviral treatment, the patients from the VISCONTI study started therapy within ten weeks of primary infection and kept it for a median of three years before treatment discontinuation (Post-Treatment Controllers or PTC). The initial analyses revealed important clinical and immunogenetic differences between post-treatment and natural controllers, suggesting that PTC were not naturally predispose to control infection and that they succeeded thanks to initial therapeutic intervention. The mechanisms associated with long-term control in post-treatment controllers also appear different from the main mechanisms identified in HIV controllers. The main objective now is to gather in a common cohort patients with a particular resistance to HIV infection, either with an immunological control (ALT) or a natural (HIV Controllers) or induced virological control (PTC). The enrolled patients will be the patients already enrolled in the cohorts CO15 and CO18, the ANRSEP47 VISCONTI study, and new patients. This will allow common physiopathological studies to precise the mechanisms leading to the virus control and CD4 homeostasy. A better knowledge of the mechanisms of viral control and immune response preservation is very important in the setting of vaccine perspectives and in the perspective of implementing new therapeutic interventions to induce remission of HIV infection. This cohort will allow common research projects with common funding, a better visibility both for clinicians who see patients with unusual phenotypes and for international research. Such a cohort will be unique in the world by its size and the presence of these three complementary groups of patients. The two main objectives for the " Extreme " cohort (ANRS CO21 CODEX) are clinical and immunovirological. We wish to precise the impact of a prolonged untreated HIV infection, to describe the frequency of the "immunological escapes" (CD4 T cell decrease) or "virological escapes" (permanent or transient viral load increase), and to identify predictive markers of HIV control. We wish to study the genetic characteristics of the patients and those of their viruses, the innate and adaptative immune responses directed against HIV and other viruses, the consequences of inflammation, and the characteristics of the loss of control.